WO 95/10516, published Apr. 20, 1995, WO96/31478, published Oct. 10, 1996, and copending application Ser. No. 09/094687 filed Jun. 15, 1998 discloses tricyclic compounds useful for inhibiting farnesyl protein transferase.
In view of the current interest in inhibitors of farnesyl protein transferase, a welcome contribution to the art would be compounds useful for the inhibition of farnesyl protein transferase. Such a contribution is provided by this invention.
This invention provides compounds useful for the inhibition of farnesyl protein transferase (FPT). The compounds of this invention are represented by the formula:
A compound of the formula: 
or a pharmaceutically acceptable salt or solvate thererof, wherein:
one of a, b, c and d represents N or N+Oxe2x88x92, and the remaining a, b, c and d groups represent CR1 or CR2; or
each of a, b, c, and d are independently selected from CR1 or CR2;
each R1 and each R2 is independently selected from H, halo, xe2x80x94CF3, xe2x80x94OR10 (e.g., xe2x80x94OCH3), xe2x80x94COR10, xe2x80x94SR10 (e.g., xe2x80x94SCH3 and xe2x80x94SCH2C6H5), xe2x80x94S(O)tR11 (wherein t is 0, 1 or 2, e.g., xe2x80x94SOCH3 and xe2x80x94SO2CH3), xe2x80x94N(R10)2, xe2x80x94NO2, xe2x80x94OC(O)R10, xe2x80x94CO2R10, xe2x80x94OCO2R11, xe2x80x94CN, xe2x80x94NR10COOR11, xe2x80x94SR11C(O)OR11 (e.g., xe2x80x94SCH2CO2CH3), xe2x80x94SR11N(R75)2 (provided that R11 in xe2x80x94SR11N(R75)2 is not xe2x80x94CH2xe2x80x94) wherein each R75 is independently selected from H or xe2x80x94C(O)OR11 (e.g., xe2x80x94S(CH2)2NHC(O)O-t-butyl and xe2x80x94S(CH2)2NH2), benzotriazol-1-yloxy, tetrazol-5-ylthio, or substituted tetrazol-5-ylthio (e.g., alkyl substituted tetrazol5-ylthio such as 1-methyl-tetrazol-5-ylthio), alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally being substituted with halo, xe2x80x94OR10 or xe2x80x94CO2R11;
R3 and R4 are the same or different and each independently represents H, any of the substituents of R1 and R2, or R3 and R4 taken together represent a saturated or unsaturated C5-C7 fused ring to the benzene ring (Ring III);
R5, R6, and R7 each independently represents H, xe2x80x94CF3, xe2x80x94COR10, alkyl or aryl, said alkyl or aryl optionally being substituted with xe2x80x94OR10, xe2x80x94SR10, xe2x80x94S(O)tR11, xe2x80x94NR10COOR11, xe2x80x94N(R10)2, xe2x80x94NO2, xe2x80x94COR10, xe2x80x94OCOR10, xe2x80x94OCO2R11, xe2x80x94CO2R10, OPO3R10, or R5 is combined with R6 to represent xe2x95x90O or xe2x95x90S; provided that for the groups xe2x80x94OR10, xe2x80x94SR10, and xe2x80x94N(R10)2 R10 is not H;
R10 represents H, alkyl, aryl, or aralkyl (e.g., benzyl);
R11 represents alkyl or aryl;
X represents N, CH or C, and when X is C the optional bond (represented by the dotted line) to carbon atom 11 is present, and when X is CH the optional bond (represented by the dotted line) to carbon atom 11 is absent;
the dotted line between carbon atoms 5 and 6 represents an optional bond, such that when a double bond is present, A and B independently represent xe2x80x94R10, halo, xe2x80x94OR11, xe2x80x94OCO2R11 or xe2x80x94OC(O)R10, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent H2, xe2x80x94(OR11)2, H and halo, dihalo, alkyl and H, (alkyl)2, xe2x80x94H and xe2x80x94OC(O)R10, H and xe2x80x94OR10, xe2x95x90O, aryl and H, xe2x95x90NOR10 or xe2x80x94Oxe2x80x94(CH2)pxe2x80x94Oxe2x80x94 wherein p is 2, 3 or 4;
R8 represents a heterocyclic ring selected from: 
said heterocyclic rings (2.0 to 7.0 and 2.1 to 7.1) being optionally substituted with one or more substituents independently selected from:
(a) alkyl (e.g., methyl, ethyl, isopropyl, and the like),
(b) substituted alkyl wherein said substituents are selected from: halo, aryl, xe2x80x94OR15 or xe2x80x94N(R15)2, heteroaryl, heterocycloalkyl, cycloalkyl, wherein each R15 group is the same or different, provided that said optional substituent is not bound to a carbon atom that is adjacent to an oxygen or nitrogen atom, and wherein R15 is selected from: H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl;
(c) hydroxyl, with the proviso that carbon atoms adjacent to the nitrogen, sulfur or oxygen atoms of the ring are not substituted with hydroxyl;
(d) alkyloxy or
(e) arylalkyloxy;
(i.e., each substitutable H atom on each substitutable carbon atom in said heterocyclic rings is optionally replaced with substituents selected from (a) to (e) defined above);
Y represents CH2, NR16, O, S, SO, or SO2 wherein R16 is selected from: H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, acyl, aroyl, carbamoyl, carboxamido, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonamido, alkylsulfonamido, arylsulfonamido and arylalkylsulfonamido;
n is 0 to 6 (preferably 1-3);
Q represents O or N, provided that Q is not adjacent to a heteroatom in the heterocycloalkyl rings of 2.1, 3.1, 4.1, 5.1, 6.1 and 7.1;
R12 is selected from: 
(e.g., R12 is 9.0);
wherein R17 is selected from: (1) H, (2) alkyl, (3) aryl, (4) arylalkyl, (5) substituted arylalkyl wherein the substituents are selected from halo (e.g., F and Cl) or CN, (6) xe2x80x94C(aryl)3 (e.g., xe2x80x94C(phenyl)3, i.e., trityl), (7) cycloalkyl, (8) substituted alkyl (as defined above in (b)), or (9) cycloalkylalkyl;
R12A is selected from rings 8.0, 8.1 or 9.1, defined above;
said imidazolyl ring 8.0 and 8.1 optionally being substituted with one or two substituents, said imidazole ring 9.0 optionally being substituted with 1-3 substituents, and said pyridyl ring 9.1 optionally being substituted with 1-4 substituents, wherein said optional substituents for rings 8.0, 8.1, 9.0 and 9.1 are bound to the carbon atoms of said rings and are independently selected from: xe2x80x94NHC(O)R15, xe2x80x94C(R18)2OR19, xe2x80x94OR15, xe2x80x94SR15, F, Cl, Br, alkyl (e.g., methyl, such as 4-methyl in 9.0), substituted alkyl (as defined above in (b)), aryl, arylalkyl, cycloalkyl, or xe2x80x94N(R15)2; R15 is as defined above; each R18 is independently selected from H or alkyl (preferably xe2x80x94CH3), preferably H; R19 is selected from H or xe2x80x94C(O)NHR20, and R20 is as defined below;
R13 and R14 for each n are independently selected from: H, F, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl or xe2x80x94CON(R15)2 (wherein R15 is as defined above), xe2x80x94OR15 or xe2x80x94N(R15)2 provided that the xe2x80x94OR15 and xe2x80x94N(R15)2 groups are not bound to a carbon atom that is adjacent to a nitrogen atom, and provided that there can be only one xe2x80x94OH group on each carbon; and the substitutable R13 and R14 groups are optionally substituted with one or more (e.g., 1-3) substituents selected from: F, alkyl (e.g., methyl, ethyl, isopropyl, and the like), cycloalkyl, arylalkyl, or heteroarylalkyl (i.e., the R13 and/or R14 groups can be unsubtituted or can be substituted with 1-3 of the substitutents described above, except when R13 and/or R14 is H); or
R13 and R14, for each n, together with the carbon atom to which they are bound, form a C3 to C6 cycloalkyl ring;
R9 is selected from: 
R20 is selected from: H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocyloalkylalkyl, provided that R20 is not H when R9 is group 12.0 or 16.0;
when R20 is other than H, then said R20 group is optionally substituted with one or more (e.g., 1-3) substituents selected from: halo, alkyl, aryl, xe2x80x94OC(O)R15 (e.g., xe2x80x94OC(O)CH3), xe2x80x94OR15 or xe2x80x94N(R15)2, wherein each R15 group is the same or different, and wherein R15 is as defined above, provided that said optional substituent is not bound to a carbon atom that is adjacent to an oxygen or nitrogen atom;
R21 is selected from: H, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
when R21 is other than H, then said R21 group is optionally substituted with one or more (e.g., 1-3) substituents selected from: alkyl, aryl, wherein each R15 group is the same or different, and wherein R15 is as defined above; and
R22 is selected from cycloalkyl (e.g., cyclopropylmethyl, i.e., 
heterocycloalkyl, aryl (e.g., phenyl), substituted aryl (e.g., halo as a substituent, such as F or Cl), alkyl (e.g., t-butyl), or substituted alkyl or substituted cycloalkyl (substituents include xe2x80x94OH, xe2x80x94CO2H, and xe2x80x94C(O)NH2).
Thus, in one embodiment of this invention R9 is 12.0. In another embodiment R9 is 13.0. In another embodiment R9 is 14.0. In another embodiment R9 is 15.0. In another embodiment R9 is 16.0.
The compounds of this invention: (i) potently inhibit farnesyl protein transferase, but not geranylgeranyl protein transferase I, in vitro; (ii) block the phenotypic change induced by a form of transforming Ras which is a farnesyl acceptor but not by a form of transforming Ras engineered to be a geranylgeranyl acceptor; (iii) block intracellular processing of Ras which is a farnesyl acceptor but not of Ras engineered to be a geranylgeranyl acceptor; and (iv) block abnormal cell growth in culture induced by transforming Ras.
The compounds of this invention inhibit farnesyl protein transferase and the farnesylation of the oncogene protein Ras. Thus, this invention further provides a method of inhibiting farnesyl protein transferase, (e.g., ras farnesyl protein transferase) in mammals, especially humans, by the administration of an effective amount of the tricyclic compounds described above. The administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase, is useful in the treatment of the cancers described below.
This invention provides a method for inhibiting or treating the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of this invention. Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs.
This invention also provides a method for inhibiting or treating tumor growth by administering an effective amount of the tricyclic compounds, described herein, to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a method for inhibiting or treating the growth of tumors expressing an activated Ras oncogene by the administration of an effective amount of the above described compounds. Examples of tumors which may be inhibited or treated include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer and prostate cancer.
It is believed that this invention also provides a method for inhibiting or treating proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genesxe2x80x94i.e., the Ras gene itself is not activated by mutation to an oncogenic formxe2x80x94with said inhibition or treatment being accomplished by the administration of an effective amount of the tricyclic compounds described herein, to a mammal (e.g., a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, lck, and fyn), may be inhibited or treated by the tricyclic compounds described herein.
The tricyclic compounds useful in the methods of this invention inhibit or treat the abnormal growth of cells. Without wishing to be bound by theory, it is believed that these compounds may function through the inhibition of G-protein function, such as ras p21, by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer. Without wishing to be bound by theory, it is believed that these compounds inhibit ras farnesyl protein transferase, and thus show antiproliferative activity against ras transformed cells.